Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3118
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FLOVENT-HFA (Aerosol, Metered)
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FLOVENT HFA
should be administered by the orally inhaled route only in patients
4 years of age and older. Individual patients will experience
a variable time to onset and degree of symptom relief. Maximum benefit
may not be achieved for 1 to 2 weeks or longer after starting
treatment. After asthma stability has been achieved,
it is always desirable to titrate to the lowest effective dosage to
reduce the possibility of side effects. For patients who do not respond
adequately to the starting dosage after 2 weeks of therapy, higher
dosages may provide additional asthma control. The safety and efficacy
of FLOVENT HFA when administered in excess of recommended dosages
have not been established. The recommended starting
dosage and the highest recommended dosage of FLOVENT HFA, based
on prior asthma therapy, are listed in Table 3. For Patients Currently Receiving Inhaled Corticosteroid
Therapy: Starting dosages above 88 mcg twice daily
may be considered for patients with poorer asthma control or those
who have previously required doses of inhaled corticosteroids that
are in the higher range for that specific agent. For Patients Currently Receiving Chronic Oral Corticosteroid Therapy: Prednisone should be reduced no faster than 2.5 to 5 mg/day
on a weekly basis, beginning after at least 1 week of therapy
with FLOVENT HFA. Patients should be carefully monitored for signs
of asthma instability, including serial objective measures of airflow,
and for signs of adrenal insufficiency (see WARNINGS). Once prednisone
reduction iscomplete, the dosage of fluticasone propionate HFA should
be reduced to the lowest effective dosage. Recommended pediatric dosage
is 88 mcg twice daily regardless of prior therapy. FLOVENT HFA should be primed before using for the first
time by releasing 4 test sprays into the air away from the face, shaking
well for 5 seconds before each spray. In cases where the inhaler has
not been used for more than 7 days or when it has been dropped,
prime the inhaler again by shaking well for 5 seconds and releasing
1 test spray into the air away from the face.<br/>Geriatric Use: In studies where geriatric patients (65 years
of age or older, see PRECAUTIONS: Geriatric Use) have been treated
with fluticasone propionate inhalation aerosol, efficacy and safety
did not differ from that in younger patients. Based on available data
for FLOVENT HFA, no dosage adjustment is recommended.<br/>Directions for Use: An Information for the Patient leaflet containing
illustrated instructions for use accompany each package of FLOVENT
HFA.
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The active component
of FLOVENT HFA 44 mcg Inhalation Aerosol, FLOVENT HFA
110 mcg Inhalation Aerosol, and FLOVENT HFA 220 mcg
Inhalation Aerosol is fluticasone propionate, a corticosteroid having
the chemical name S-(fluoromethyl)
6��,9-difluoro-11��,17-dihydroxy-16��-methyl-3-oxoandrosta-1,4-diene-17��-carbothioate,
17-propionate and the following chemical structure: Fluticasone propionate is a white powder with a molecular
weight of 500.6, and the empirical formula is CHFOS. It is practically insoluble
in water, freely soluble in dimethyl sulfoxide and dimethylformamide,
and slightly soluble in methanol and 95% ethanol. FLOVENT HFA 44 mcg Inhalation Aerosol, FLOVENT HFA
110 mcg Inhalation Aerosol, and FLOVENT HFA 220 mcg
Inhalation Aerosol are pressurized metered-dose aerosol units fitted
with a counter. FLOVENT HFA is intended for oral inhalation only.
Each unit contains a microcrystalline suspension of fluticasone propionate
(micronized) in propellant HFA-134a (1,1,1,2-tetrafluoroethane). It
contains no other excipients. After priming,
each actuation of the inhaler delivers 50, 125, or 250 mcg of
fluticasone propionate in 60 mg of suspension (for the 44-mcg
product) or in 75 mg of suspension (for the 110- and 220-mcg
products) from the valve. Each actuation delivers 44, 110, or 220 mcg
of fluticasone propionate fromthe actuator. The actual amount of
drug delivered to the lung may depend on patient factors, such as
the coordination between the actuation of the device and inspiration
through the delivery system. Each 10.6-g canister
(44 mcg) and each 12-g canister (110 and 220 mcg) provides
120 inhalations. FLOVENT HFA should be
primed before using for the first time by releasing 4 test sprays
into the air away from the face, shaking well for 5 seconds before
each spray. In cases where the inhaler has not been used for more
than 7 days or when it has been dropped, prime the inhaler again
by shaking well for 5 seconds and releasing 1 test spray into
the air away from the face. This product does
not contain any chlorofluorocarbon (CFC) as the propellant.
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Mechanism of Action: Fluticasone propionate is a synthetic trifluorinated
corticosteroid with potent anti-inflammatory activity. In vitro assays
using human lung cytosol preparations have established fluticasone
propionate as a human glucocorticoid receptor agonist with an affinity
18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate
(BMP), the active metabolite of beclomethasone dipropionate, and over
3 times that of budesonide. Data from the McKenzie vasoconstrictor
assay in man are consistent with these results. The clinical significance
of these findings is unknown. Inflammation is
an important component in the pathogenesis of asthma. Corticosteroids
have been shown to inhibit multiple cell types (e.g., mast cells,
eosinophils, basophils, lymphocytes, macrophages, and neutrophils)
and mediator production or secretion (e.g., histamine, eicosanoids,
leukotrienes, and cytokines) involved in the asthmatic response. These
anti-inflammatory actions of corticosteroids contribute to their efficacy
in asthma. Though effective for the treatment
of asthma, corticosteroids do not affect asthma symptoms immediately.
Individual patients will experience a variable time to onset and degree
of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks
or longer after starting treatment. When corticosteroids are discontinued,
asthma stability may persist for several days or longer. Studies in patients with asthma have shown a favorable
ratio between topical anti-inflammatory activity and systemic corticosteroid
effects with recommended doses of orally inhaled fluticasone propionate.
This is explained by a combination of a relatively high local anti-inflammatory
effect, negligible oral systemic bioavailability (<1%), and the
minimal pharmacological activity of the only metabolite detected in
man.<br/>Preclinical: In animals and humans, propellant HFA-134a was found
to be rapidly absorbed and rapidly eliminated, with an elimination
half-life of 3 to 27 minutes in animals and 5 to 7 minutes
in humans. Time to maximum plasma concentration (T)
and mean residence time are both extremely short, leading to a transient
appearance of HFA-134a in the blood with no evidence of accumulation. Propellant HFA-134a is devoid of pharmacological activity
except at very high doses in animals (i.e., 380 to 1,300 times the
maximum human exposure based on comparisons of area under the plasma
concentration versus time curve [AUC] values), primarily producing
ataxia, tremors, dyspnea, or salivation. These events are similar
to effects produced by the structurally related CFCs, which have been
used extensively in metered-dose inhalers.<br/>Pharmacokinetics:<br/>Absorption: Fluticasone propionate acts locally in the lung;
therefore, plasma levels do not predict therapeutic effect. Studies
using oral dosing of labeled and unlabeled drug have demonstrated
that the oral systemic bioavailability of fluticasone propionate is
negligible (<1%), primarily due to incomplete absorption and presystemic
metabolism in the gut and liver. In contrast, the majority of the
fluticasone propionate delivered to the lung is systemically absorbed.
Systemic exposure as measured by AUC in healthy subjects (N = 24)
who received 8 inhalations, as a single dose, of fluticasone
propionate HFA using the 44-, 110-, and 220-mcg strengths increased
proportionally with dose. The geometric means (95% CI) of AUCfor the 44-, 110-, and 220-mcg strengths were 488 (362,
657); 1,284 (904; 1,822); and 2,495 (1,945; 3,200) pg���hr/mL,
respectively, and the geometric means of Cwere 126
(108, 148), 254 (202, 319), and 421 (338, 524) pg/mL, respectively.
Systemic exposure from fluticasone propionate HFA 220 mcg was
30% lower than that from the fluticasone propionate CFC inhaler. Systemic
exposure was measured in patients with asthma who received 2 inhalations
of fluticasone propionate HFA 44 mcg (n = 20), 110 mcg
(n = 15), or 220 mcg (n = 17) twice daily
for at least 4 weeks. The geometric means (95% CI) of AUCfor the 44-, 110-, and 220-mcg strengths were 76 (33,
175), 298 (191, 464), and 601 (431, 838) pg���hr/mL, respectively.
Coccurred in about 1 hour, and the geometric means
were 25 (18, 36), 61 (46, 81), and 103 (73, 145) pg/mL, respectively.<br/>Distribution: Following intravenous administration, the initial
disposition phase for fluticasone propionate was rapid and consistent
with its high lipid solubility and tissue binding. The volume of distribution
averaged 4.2 L/kg. The percentage of fluticasone
propionate bound to human plasma proteins averages 99%. Fluticasone
propionate is weakly and reversibly bound to erythrocytes and is not
significantly bound to human transcortin.<br/>Metabolism: The total clearance
of fluticasone propionate is high (average, 1,093 mL/min), with
renal clearance accounting for less than 0.02% of the total. The only
circulating metabolite detected in man is the 17��-carboxylic
acid derivative of fluticasone propionate, which is formed through
the cytochrome P450 3A4 pathway. This metabolite had less affinity
(approximately 1/2,000) than the parent drug for the corticosteroid
receptor of human lung cytosol in vitro and negligible pharmacological
activity in animal studies. Other metabolites detected in vitro using
cultured human hepatoma cells have not been detected in man.<br/>Elimination: Following intravenous
dosing, fluticasone propionate showed polyexponential kinetics and
had a terminal elimination half-life of approximately 7.8 hours.
Less than 5% of a radiolabeled oral dose was excreted in the urine
as metabolites, with the remainder excreted in the feces as parent
drug and metabolites.<br/>Special Populations:<br/>Drug Interactions: Fluticasone propionate is a substrate of cytochrome
P450 3A4. Coadministration of fluticasone propionate and the highly
potent cytochrome P450 3A4 inhibitor ritonavir is not recommended
based upon a multiple-dose, crossover drug interaction study in 18
healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg
once daily) was coadministered for 7 days with ritonavir (100 mg
twice daily). Plasma fluticasone propionate concentrations following
fluticasone propionate aqueous nasal spray alone were undetectable
(<10 pg/mL) in most subjects, and when concentrations were
detectable, peak levels (C) averaged 11.9 pg/mL (range,
10.8 to 14.1 pg/mL) and AUCaveraged 8.43 pg���hr/mL
(range, 4.2 to 18.8 pg���hr/mL). Fluticasone propionate
Cand AUCincreased to 318 pg/mL
(range, 110 to 648 pg/mL) and 3,102.6 pg���hr/mL (range,1,207.1 to 5,662.0 pg���hr/mL), respectively, after coadministration
of ritonavir with fluticasone propionate aqueous nasal spray. This
significant increase in plasma fluticasone propionate exposure resulted
in a significant decrease (86%) in serum cortisol AUC. Caution should be exercised when other potent cytochrome
P450 3A4 inhibitors are coadministered with fluticasone propionate.
In a drug interaction study, coadministration of orally inhaled fluticasone
propionate (1,000 mcg) and ketoconazole (200 mg once daily)
resulted in increased systemic fluticasone propionate exposure and
reduced plasma cortisol AUC, but had no effect on urinary excretion
of cortisol. In another multiple-dose drug
interaction study, coadministration of orally inhaled fluticasone
propionate (500 mcg twice daily) and erythromycin (333 mg
3 times daily) did not affect fluticasone propionate pharmacokinetics. Similar definitive studies with fluticasone propionate
HFA were not performed, but results should be independent of the formulation
and drug delivery device.<br/>Pharmacodynamics: Serum cortisol
concentrations, urinary excretion of cortisol, and urine 6-��-hydroxycortisol
excretion collected over 24 hours in 24 healthy subjects following
8 inhalations of fluticasone propionate HFA 44, 110, and 220 mcg
decreased with increasing dose. However, in patients with asthma treated
with 2 inhalations of fluticasone propionate HFA 44, 110, and
220 mcg twice daily for at least 4 weeks, differences
in serum cortisol AUCconcentrations (n = 65)
and 24-hour urinary excretion of cortisol (n = 47) compared
with placebo were not related to dose and generally not significant.
In the study with healthy volunteers, the effect of propellant was
also evaluated by comparing results following the 220-mcg strength
inhaler containing HFA 134a propellant with the same strength of inhaler
containing CFC 11/12 propellant. A lesser effect on the hypothalamic-pituitary-adrenal
(HPA) axis with the HFA formulation was observed for serum cortisol,
but not urine cortisol and 6-betahydroxy cortisol excretion. In addition,
in a crossover study of children with asthma aged 4 to 11 years (N = 40),
24-hour urinary excretion of cortisol was not affected after a 4-week
treatment period with 88 mcg of fluticasone propionate HFA twice
daily compared with urinary excretion after the 2-week placebo period.
The ratio (95% CI) of urinary excretion of cortisol over 24 hours
following fluticasone propionate HFA versus placebo was 0.987 (0.796,
1.223).(See PRECAUTIONS: Pediatric Use for pharmacodynamic information
on children aged 6 months to<4 years.) The
potential systemic effects of fluticasone propionate HFA on the HPA
axis were also studied in patients with asthma. Fluticasone propionate
given by inhalation aerosol at dosages of 440 or 880 mcg twice
daily was compared with placebo in oral corticosteroid-dependent patients
with asthma (range of mean dose of prednisone at baseline, 13 to 14 mg/day)
in a 16-week study. Consistent with maintenance treatment with oral
corticosteroids, abnormal plasma cortisol responses to short cosyntropin
stimulation (peak plasma cortisol<18 mcg/dL) were present
at baseline in the majority of patients participating in this study
(69% of patients later randomized to placebo and 72% to 78% of patients
later randomized to fluticasone propionate HFA). At week 16, 8 patients
(73%) on placebo compared to 14 (54%) and 13 (68%) patients receiving
fluticasone propionate HFA (440 and 880 mcg b.i.d., respectively)
had post-stimulation cortisol levels of<18 mcg/dL. To confirm that systemic absorption does not play a role
in the clinical response to inhaled fluticasone propionate, a double-blind
clinical study comparing inhaled fluticasone propionate powder and
oral fluticasone propionate was conducted. Fluticasone propionate
inhalation powder in dosages of 100 and 500 mcg twice daily was
compared to oral fluticasone propionate 20,000 mcg once daily
and placebo for 6 weeks. Plasma levels of fluticasone propionate
were detectable in all 3 active groups, but the mean values were highest
in the oral group. Both dosages of inhaled fluticasone propionate
were effective in maintaining asthma stability and improving lung
function, while oral fluticasone propionate and placebo were ineffective.
This demonstrates that the clinical effectiveness of inhaled fluticasone
propionate is due to its direct local effect and not to an indirect
effect through systemic absorption.
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FLOVENT HFA Inhalation
Aerosol is contraindicated in the primary treatment of status asthmaticus
or other acute episodes of asthma where intensive measures are required. Hypersensitivity to any of the ingredients of these preparations
contraindicates their use (see DESCRIPTION).
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FLOVENT HFA 44 mcg Inhalation Aerosol is supplied
in 10.6-g pressurized aluminum canisters containing 120 metered actuations
in boxes of 1 (NDC 0173-0718-20). FLOVENT HFA
110 mcg Inhalation Aerosol is supplied in 12-g pressurized aluminum
canisters containing 120 metered actuations in boxes of 1 (NDC 0173-0719-20). FLOVENT HFA 220 mcg Inhalation Aerosol is supplied
in 12-g pressurized aluminum canisters containing 120 metered actuations
in boxes of 1 (NDC 0173-0720-20). Each canister
is fitted with a dose counter, supplied with a dark orange oral actuator
with a peach strapcap, and sealed in a plastic coated, moisture protective
foil pouch with a desiccant that should be discarded when the pouch
is opened. Each canister is packaged with an Information for the Patient
leaflet. The dark orange actuator supplied with FLOVENT HFA should not be
used with any other product canisters, and actuators from other products
should not be used with a FLOVENT HFA canister. The correct amount of medication
in each actuation cannot be assured after the counter reads 000, even
though the canister is not completely empty and will continue to operate.
The inhaler should be discarded when the counter reads 000. Keep out of reach
of children. Avoid spraying in eyes. Contents Under Pressure: Do not puncture.
Do not use or store near heat or open flame. Exposure to temperatures
above 120��F may cause bursting. Never throw into fire or incinerator. Store at 25��C
(77��F); excursions permitted to 15��-30��C (59��-86��F).
Store the inhaler with the mouthpiece down. For best results, the
inhaler should be at room temperature before use. SHAKE WELL FOR 5
SECONDS BEFORE USING. FLOVENT
HFA does not contain chlorofluorocarbons (CFCs) as the propellant. DISKUS, FLOVENT, ROTADISK, and VENTOLIN are registered
trademarks of GlaxoSmithKline. AeroChamber Plus
is a registered trademark and AeroChamber Z-STAT Plus is a trademark
of Monaghan Medical Corp. or an affiliate of Monaghan Medical Corp. GlaxoSmithKline Research Triangle
Park, NC 27709 ��2008, GlaxoSmithKline.
All rights reserved. July 2008 FLH:1PI PHARMACIST���DETACH HERE AND GIVE LEAFLET TO PATIENT Information for
the Patient FLOVENT [fl�����vent] HFA 44 mcg (fluticasone propionate
44 mcg) Inhalation Aerosol FLOVENT HFA 110 mcg (fluticasone propionate 110 mcg) Inhalation Aerosol FLOVENT HFA 220 mcg (fluticasone propionate 220
mcg) Inhalation
Aerosol FOR ORAL INHALATION ONLY Read this
leaflet carefully before you start to use FLOVENT HFA Inhalation Aerosol. Keep this leaflet because it has important summary information
about FLOVENT HFA. This leaflet does not contain all the information
about your medicine. If you have any questions or are not sure about
something, you should ask your doctor or pharmacist. Read the new leaflet that comes with each refill of your prescription
because there may be new information. What is FLOVENT HFA? FLOVENT HFA contains a medicine called fluticasone propionate, which
is a synthetic corticosteroid. Corticosteroids are natural substances
found in the body that help fight inflammation. Corticosteroids are
used to treat asthma because they reduce airway inflammation. FLOVENT HFA is used to treat asthma in patients 4 years
of age and older. When inhaled regularly, FLOVENT HFA also helps to
prevent symptoms of asthma. FLOVENT HFA comes
in 3 strengths. Your doctor has prescribed the one that is best for
your condition. Who
should not use FLOVENT HFA? Do not
use FLOVENT HFA if you: What should I tell my
doctor before taking FLOVENT HFA? Tell your doctor if you are: Tell your doctor about all the medicines you take
including prescription and non-prescription medicines, vitamins, and
herbal supplements. FLOVENT HFA may affect the way other medicines
work, and other medicines may affect how FLOVENT HFA works. Especially,
tell your doctor if you take: How should I use FLOVENT
HFA? What are the possible
side effects of FLOVENT HFA? Common
side effects in adults and children using FLOVENT HFA include: Other common side effects in children include: Tell your doctor if you have any side effect that
bothers you or that does not go away. These are not all the possible
side effects of FLOVENT HFA. For more information ask your doctor
or pharmacist. Call your doctor for medical
advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What are the ingredients in
FLOVENT HFA? Active ingredient: fluticasone
propionate (micronized) Inactive ingredient:
propellant HFA-134a Instructions for Using FLOVENT HFA The parts of your FLOVENT HFA There are 2 main parts to your FLOVENT HFA
inhaler���the metal canister that holds the medicine and the
dark orange plastic actuator that sprays the medicine from the canister
(see Figure 1). The canister has a counter to show
how many sprays of medicine you have left. The number shows through
a window in the back of the actuator. The counter starts at 124. The
number will count down by 1 each time you spray the inhaler. The counter
will stop counting at 000. Never try to change the numbers or take the counter
off the metal canister. The counter cannot be reset, and
it is permanently attached to the canister. The mouthpiece of the actuator is covered by a cap. A strap on this
cap keeps it attached to the actuator. Do not use the actuator with a canister of medicine
from any other inhaler. And do not use a FLOVENT HFA canister with
an actuator from any other inhaler. Using your FLOVENT HFA Before you use FLOVENT
HFA for the first time, you must prime the inhaler so that you will
get the right amount of medicine when you use it. To prime
the inhaler, take the cap off the mouthpiece and shake the inhaler
well for 5 seconds. Then spray the inhaler into the air away
from your face. Avoid spraying in eyes. Shake and spray the inhaler like this 3 more times to finish priming
it. The counter should now read 120. You must
prime the inhaler again if you have not used it in more than 7 days
or if you drop it. Take the cap off the mouthpiece and shake the inhaler
well for 5 seconds. Then spray it 1 time into the air away from your
face. Read the following 7 steps before using FLOVENT HFA and follow them at each use. If you have any
questions, ask your doctor or pharmacist. Cleaning your FLOVENT
HFA Clean the inhaler at least once
a week after your evening dose. It is important
to keep the canister and plastic actuator clean so the medicine will
not build-up and block the spray. Storing your FLOVENT HFA Store at room temperature
with the mouthpiece down. Keep out
of reach of children. Contents Under Pressure: Do not puncture. Do not use or
store near heat or open flame. Exposure to temperatures above 120��F
may cause bursting. Never throw into fire or incinerator. Replacing your FLOVENT HFA For more information go to www.floventdiskus.com
or call 1-888-825-5249. FLOVENT is a registered
trademark of GlaxoSmithKline. NORVIR and KALETRA are registered trademarks of Abbott Laboratories. GlaxoSmithKline Research Triangle
Park, NC 27709 ��2008, GlaxoSmithKline.
All rights reserved. July 2008 FLH:1PIL
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General: Orally inhaled corticosteroids may cause a reduction
in growth velocity when administered to pediatric patients (see PRECAUTIONS:
Pediatric Use). Fluticasone propionate will
often help control asthma symptoms with less suppression of HPA function
than therapeutically equivalent oral doses of prednisone. Since fluticasone
propionate is absorbed into the circulation and can be systemically
active at higher doses, the beneficial effects of FLOVENT HFA
in minimizing HPA dysfunction may be expected only when recommended
dosages are not exceeded and individual patients are titrated to the
lowest effective dose. A relationship between plasma levels of fluticasone
propionate and inhibitory effects on stimulated cortisol production
has been shown after 4 weeks of treatment with fluticasone propionate
inhalation aerosol. Since individual sensitivity to effects on cortisol
production exists, physicians should consider this information when
prescribing FLOVENT HFA. Because of the
possibility of systemic absorption of inhaled corticosteroids, patients
treated with FLOVENT HFA should be observed carefully for any
evidence of systemic corticosteroid effects. Particular care should
be taken in observing patients postoperatively or during periods of
stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism
and adrenal suppression (including adrenal crisis) may appear in a
small number of patients, particularly when FLOVENT HFA is administered
at higher than recommended doses over prolonged periods of time. If
such effects occur, the dosage of FLOVENT HFA should be reduced
slowly, consistent with accepted procedures for reducing systemic
corticosteroids and for management of asthma. The long-term effects of FLOVENT HFA in human subjects are not
fully known. In particular, the effects resulting from chronic use
of fluticasone propionate on developmental or immunologic processes
in the mouth, pharynx, trachea, and lung are unknown. Some patients
have received inhaled fluticasone propionate on a continuous basis
in a clinical study for up to 4 years. In clinical studies with patients
treated for 2 years with inhaled fluticasone propionate, no apparent
differences in the type or severity of adverse reactions were observed
after long- versus short-term treatment. Glaucoma,
increased intraocular pressure, and cataracts have been reported in
patients following the long-term administration of inhaled corticosteroids,
including fluticasone propionate. In clinical
studies with inhaled fluticasone propionate, the development of localized
infections of the pharynx with Candida
albicans has occurred. When such an infection develops,
it should be treated with appropriate local or systemic (i.e., oral
antifungal) therapy while remaining on treatment with FLOVENT HFA,
but at times therapy with FLOVENT HFA may need to be interrupted. Inhaled corticosteroids should be used with caution, if
at all, in patients with active or quiescent tuberculosis infection
of the respiratory tract; untreated systemic fungal, bacterial, viral
or parasitic infections; or ocular herpes simplex.<br/>Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate
may present with systemic eosinophilic conditions, with some patients
presenting with clinical features of vasculitis consistent with Churg-Strauss
syndrome, a condition that is often treated with systemic corticosteroid
therapy. These events usually, but not always, have been associated
with the reduction and/or withdrawal of oral corticosteroid therapy
following the introduction of fluticasone propionate. Cases of serious
eosinophilic conditionshave also been reported with other inhaled
corticosteroids in this clinical setting. Physicians should be alert
to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac
complications, and/or neuropathy presenting in their patients. A causal
relationship between fluticasone propionate and these underlying conditions
has not been established (see ADVERSE REACTIONS: Observed During Clinical
Practice: Eosinophilic Conditions).<br/>Information for Patients: Patients being
treated with FLOVENT HFA should receive the following information
and instructions. This information is intended to aid them in the
safe and effective use of this medication. It is not a disclosure
of all possible adverse or intended effects. It is important that
patients understand how to use FLOVENT HFA in relation to other
asthma medications they are taking.<br/>Drug Interactions:<br/>Inhibitors of Cytochrome P450: Fluticasone propionate is a substrate of cytochrome
P450 3A4. A drug interaction study with fluticasone propionate aqueous
nasal spray in healthy subjects has shown that ritonavir (a highly
potent cytochrome P450 3A4 inhibitor) can significantly increase plasma
fluticasone propionate exposure, resulting in significantly reduced
serum cortisol concentrations (see CLINICAL PHARMACOLOGY: Pharmacokinetics: Drug Interactions ). During postmarketing
use, there have been reports of clinically significant drug interactions
in patients receiving fluticasone propionate and ritonavir, resulting
in systemic corticosteroid effects including Cushing syndrome and
adrenal suppression. Therefore, coadministration of fluticasone propionate
and ritonavir is not recommended unless the potential benefit to the
patient outweighs the risk of systemic corticosteroid side effects. In a placebo-controlled crossover study in 8 healthy adult
volunteers, coadministration of a single dose of orally inhaled fluticasone
propionate (1,000 mcg) with multiple doses of ketoconazole (200 mg)
to steady state resulted in increased systemic fluticasone propionate
exposure, a reduction in plasma cortisol AUC, and no effect on urinary
excretion of cortisol. Caution should be exercised when FLOVENT HFA
is coadministered with ketoconazole and other known potent cytochrome
P450 3A4 inhibitors.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility: Fluticasone propionate demonstrated no tumorigenic
potential in mice at oral doses up to 1,000 mcg/kg (approximately
2 and 10 times the maximum recommended human daily inhalation
dose in adults and children, respectively, on a mcg/mbasis)
for 78 weeks or in rats at inhalation doses up to 57 mcg/kg
(less than and equivalent to the maximum recommended human daily inhalation
dose in adults and children, respectively, on a mcg/mbasis)
for 104 weeks. Fluticasone propionate
did not induce gene mutation in prokaryotic or eukaryotic cells in
vitro. No significant clastogenic
effect was seen in cultured human peripheral lymphocytes in vitro
or in the mouse micronucleus test. No evidence
of impairment of fertility was observed in reproductive studies conducted
in male and female rats at subcutaneous doses up to 50 mcg/kg
(less than the maximum recommended human daily inhalation dose on
a mcg/mbasis). Prostate weight was significantly reduced
at a subcutaneous dose of 50 mcg/kg.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy
Category C. Subcutaneous studies in the mouse and rat at 45 and 100 mcg/kg,
respectively (less than the maximum recommended human daily inhalation
dose on a mcg/mbasis), revealed fetal toxicity characteristic
of potent corticosteroid compounds, including embryonic growth retardation,
omphalocele, cleft palate, and retarded cranial ossification. No teratogenicity
was seen in the rat at inhalation doses up to 68.7 mcg/kg (less
than the maximum recommended human daily inhalation dose on a mcg/mbasis). In the rabbit, fetal weight
reduction and cleft palate were observed at a subcutaneous dose of
4 mcg/kg (less than the maximum recommended human daily inhalation
dose on a mcg/mbasis). However, no teratogenic effects
were reported at oral doses up to 300 mcg/kg (approximately 3 times
the maximum recommended human daily inhalation dose on a mcg/mbasis) of fluticasone propionate. No fluticasone propionate
was detected in the plasma in this study, consistent with the established
low bioavailability following oral administration (see CLINICAL PHARMACOLOGY:
Pharmacokinetics: Absorption ). Fluticasone propionate crossed the placenta
following administration of a subcutaneous dose of 100 mcg/kg
to mice (less than the maximum recommended human daily inhalation
dose on a mcg/mbasis), a subcutaneous or an oral dose
of 100 mcg/kg to rats (less than the maximum recommended daily
inhalation dose on a mcg/mbasis), and an oral dose of
300 mcg/kg to rabbits (approximately 3 times the maximum
recommended human daily inhalation dose on a mcg/mbasis). There are no adequate and well-controlled studies in pregnant
women. FLOVENT HFA should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction
in pharmacologic, as opposed to physiologic, doses suggests that rodents
are more prone to teratogenic effects from corticosteroids than humans.
In addition, because there is a natural increase in corticosteroid
production during pregnancy, most women will require a lower exogenous
corticosteroid dose and many will not need corticosteroid treatment
during pregnancy.<br/>Nursing Mothers: It is not known whether fluticasone propionate is
excreted in human breast milk. However, other corticosteroids have
been detected in human milk. Subcutaneous administration to lactating
rats of 10 mcg/kg tritiated fluticasone propionate (less than
the maximum recommended human daily inhalation dose on a mcg/mbasis) resulted in measurable radioactivity in milk. Since there are no data from controlled trials on the
use of FLOVENT HFA by nursing mothers, a decision should be made
whether to discontinue nursing or to discontinue FLOVENT HFA,
taking into account the importance of FLOVENT HFA to the mother. Caution should be exercised when FLOVENT HFA is administered
to a nursing woman.<br/>Pediatric Use: The safety and effectiveness of FLOVENT HFA in children
12 years of age and older have been established (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Special Populations: Pediatric, CLINICAL TRIALS: Pediatric
Patients, ADVERSE REACTIONS: Pediatric Patients). Use of FLOVENT HFA
in patients 4 to 11 years of age is supported by evidence from
adequate and well-controlled studies in adults and adolescents 12 years
of age and older, pharmacokinetic studies in patients 4 to 11 years
of age, established efficacy of fluticasone propionate formulated
as FLOVENT DISKUS (fluticasone propionate
inhalation powder) and FLOVENT ROTADISK (fluticasone propionate inhalation powder) in patients 4 to 11 years
of age, and supportive findings with FLOVENT HFA in a study conducted
in patients 4 to 11 years of age. Types of adverse events in
pediatric patients 4 to 11 years of age were generally similar
to those observed in adults and adolescents.<br/>Children Less Than 4 Years
of Age:<br/>Geriatric Use: Of the total number of patients treated with FLOVENT
HFA in US and non-US clinical trials, 173 were 65 years of age
or older, 19 of which were 75 years of age or older. No apparent
differences in safety or efficacy were observed between these patients
and younger patients. No overall differences in safety were observed
between these patients and younger patients, and other reported clinical
experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out. In general, dose selection for an
elderly patient should be cautious, reflecting the greater frequency
of decreased hepatic function and of concomitant disease or other
drug therapy.
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| dailymed-instance:overdosag... |
Chronic overdosage may result in signs/symptoms of
hypercorticism (see PRECAUTIONS: General). Inhalation by healthy volunteers
of a single dose of 1,760 or 3,520 mcg of fluticasone propionate
CFC inhalation aerosol was well tolerated. Doses of 1,320 mcg
administered to healthy human volunteers twice daily for 7 to 15 days
were also well tolerated. Repeat oral doses up to 80 mg daily
for 10 days in healthy volunteers and repeat oral doses up to
20 mg daily for 42 days in patients were well tolerated.
Adverse reactions were of mild or moderate severity, and incidences
were similar in active and placebo treatment groups. The oral median
lethal dose in mice was>1,000 mg/kg (approximately���2,300
and>11,000 times the maximum human daily inhalation dose in adults
and children on a mg/mbasis, respectively), and the subcutaneous
median lethal dose in rats was>1,000 mg/kg (approximately>4,600
and>22,000 times the maximum human daily inhalation dose in adults
and children on a mg/mbasis, respectively).
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| dailymed-instance:genericMe... |
fluticasone propionate
|
| dailymed-instance:fullName |
FLOVENT-HFA (Aerosol, Metered)
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| dailymed-instance:adverseRe... |
Adolescent and Adult Patients: The incidence
of common adverse events in Table 2 is based upon 2 placebo-controlled
US clinical trials in which 812 adolescent and adult patients (457 females
and 355 males) previously treated with as-needed bronchodilators
and/or inhaled corticosteroids were treated twice daily for up to
12 weeks with 2 inhalations of FLOVENT HFA 44 mcg Inhalation Aerosol,
FLOVENT HFA 110 mcg Inhalation Aerosol, FLOVENT HFA 220 mcg Inhalation
Aerosol (dosages of 88, 220, or 440 mcg twice daily) or placebo. Table 2 includes all events (whether considered
drug-related or nondrug-related by the investigator) that occurred
at a rate of over 3% in any of the groups treated with FLOVENT HFA
and were more common than in the placebo group. In considering these
data, differences in average duration of exposure should be taken
into account. These adverse events were mostly
mild to moderate in severity. Rare cases of immediate and delayed
hypersensitivity reactions, including urticaria and rash, have been
reported. Other adverse events that occurred
in the groups receiving FLOVENT HFA in these studies with an
incidence of 1% to 3% and that occurred at a greater incidence than
with placebo were:<br/>Ear, Nose, and Throat: Sinusitis/sinus infection, rhinitis, pharyngitis/throat
infection, rhinorrhea/post-nasal drip, nasal sinus disorders, laryngitis.<br/>Gastrointestinal: Diarrhea, viral gastrointestinal infections, gastrointestinal
signs and symptoms, dyspeptic symptoms, gastrointestinal discomfort
and pain, hyposalivation.<br/>Musculoskeletal: Musculoskeletal pain, muscle pain, muscle stiffness/tightness/rigidity.<br/>Neurological: Dizziness, migraines.<br/>Non-Site Specific: Fever, viral
infections, pain, chest symptoms.<br/>Skin: Viral skin infections.<br/>Trauma: Muscle injuries, soft tissue injuries, injuries.<br/>Urogenital: Urinary infections. Fluticasone
propionate inhalation aerosol (440 or 880 mcg twice daily) was
administered for 16 weeks to patients with asthma requiring oral
corticosteroids (Study 3). Adverse events not included in Table 2,
but reported by>3 patients in either group treated with FLOVENT HFA
and more commonly than in the placebo group included rhinitis, nausea
and vomiting, arthralgia and articular rheumatism, musculoskeletal
pain, muscle pain, malaise and fatigue, and sleep disorders. In 2 long-term studies (26 and 52 weeks), treatment
with FLOVENT HFA at dosages up to 440 mcg twice daily was
well tolerated. The pattern of adverse events was similar to that
observed in the 12-week studies. There were no new and/or unexpected
adverse events with long-term treatment.<br/>Pediatric Patients: FLOVENT HFA has been evaluated for safety in 56
pediatric patients aged 4 to 11 years who received 88 mcg
twice daily for 4 weeks. Types of adverse events in these pediatric
patients were generally similar to those observed in adults and adolescents.<br/>Observed During Clinical Practice: In addition to adverse events reported from clinical
trials, the following events have been identified during postmarketing
use of fluticasone propionate. Because they are reported voluntarily
from a population of unknown size, estimates of frequency cannot be
made. These events have been chosen for inclusion due to a combination
of heir seriousness, frequency of reporting, or potential causal connection
to fluticasone propionate.<br/>Ear, Nose, and Throat: Aphonia, facial and oropharyngeal edema, including
angioedema, and throat soreness and irritation.<br/>Endocrine and Metabolic: Cushingoid features, growth velocity reduction in
children/adolescents, hyperglycemia, osteoporosis, and weight gain.<br/>Eye: Cataracts.<br/>Non-Site Specific: Very rare anaphylactic reaction.<br/>Psychiatry: Agitation, aggression, anxiety, depression, and
restlessness. Behavioral changes, including hyperactivity and irritability,
have been reported very rarely and primarily in children.<br/>Respiratory: Asthma exacerbation, chest tightness, cough, dyspnea,
immediate and delayed bronchospasm, paradoxical bronchospasm, pneumonia,
and wheeze.<br/>Skin: Contusions, cutaneous hypersensitivity reactions,
ecchymoses, and pruritus.<br/>Eosinophilic Conditions: In rare cases, patients on inhaled fluticasone propionate
may present with systemic eosinophilic conditions, with some patients
presenting with clinical features of vasculitis consistent with Churg-Strauss
syndrome, a condition that is often treated with systemic corticosteroid
therapy. These events usually, but not always, have been associated
with the reduction and/or withdrawal of oral corticosteroid therapy
following the introduction of fluticasone propionate (see PRECAUTIONS:
Eosinophilic Conditions).
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| dailymed-instance:warning |
1. Transferring patients
from systemic corticosteroid therapy. Particular care is
needed for patients who have been transferred from systemically active
corticosteroids to inhaled corticosteroids because deaths due to adrenal
insufficiency have occurred in patients with asthma during and after
transfer from systemic corticosteroids to less systemically available
inhaled corticosteroids. After withdrawal from systemic corticosteroids,
a number of months are required for recovery of HPA function. Patients requiring oral corticosteroids should be weaned
slowly from systemic corticosteroid use after transferring to FLOVENT HFA.
In a clinical trial of 168 patients, prednisone reduction was successfully
accomplished by reducing the daily prednisone dose on a weekly basis
following initiation of treatment with FLOVENT HFA. Successive
reduction of prednisone dose was allowed only when lung function;
symptoms;and as-needed, short-acting beta-agonist use were better
than or comparable to that seen before initiation of prednisone dose
reduction. Lung function (FEVor AM PEF), beta-agonist
use, and asthma symptoms should be carefully monitored during withdrawal
of oral corticosteroids. In addition to monitoring asthma signs and
symptoms, patients should be observed for signs and symptoms of adrenal
insufficiency such as fatigue, lassitude, weakness, nausea and vomiting,
and hypotension. Patients who have been previously
maintained on 20 mg or more per day of prednisone (or its equivalent)
may be most susceptible, particularly when their systemic corticosteroids
have been almost completely withdrawn. During this period of HPA suppression,
patients may exhibit signs and symptoms of adrenal insufficiency when
exposed to trauma, surgery, or infection (particularly gastroenteritis)
or other conditions associated with severe electrolyte loss. Although
inhaled corticosteroids may provide control of asthma symptoms during
these episodes, in recommended doses they supply less than normal
physiological amounts of glucocorticoid (cortisol) systemically and
do NOT provide the mineralocorticoid activity that is necessary for
coping with these emergencies. During periods
of stress or a severe asthma attack, patients who have been withdrawn
from systemic corticosteroids should be instructed to resume oralcorticosteroids (in large doses) immediately and to contact their
physicians for further instruction. These patients should also be
instructed to carry a warning card indicating that they may need supplementary
systemic corticosteroids during periods of stress or a severe asthma
attack. Transfer of patients from systemic corticosteroid
therapy to FLOVENT HFA may unmask conditions previously suppressed
by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis,
eczema, arthritis, and eosinophilic conditions. Some patients may
experience symptoms of systemically active corticosteroid withdrawal,
e.g., joint and/or muscular pain, lassitude, and depression, despite
maintenance or even improvement of respiratory function. 2. Bronchospasm. As with other inhaled medications, bronchospasm may occur with an
immediate increase in wheezing after dosing. If bronchospasm occurs
following dosing with FLOVENT HFA, it should be treated immediately
with a fast-acting inhaled bronchodilator. Treatment with FLOVENT HFA
should be discontinued andalternative therapy instituted. Patients should be instructed to contact their physicians
immediately when episodes of asthma that are not responsive to bronchodilators
occur during the course of treatment with FLOVENT HFA. During
such episodes, patients may require therapy with oral corticosteroids. 3. Immunosuppression. Persons who are using drugs that suppress the immune system are
more susceptible to infections than healthy individuals. Chickenpox
and measles, for example, can have a more serious or even fatal coursein susceptible children or adults using corticosteroids. In such children
or adults who have not had these diseases or been properly immunized,
particular care should be taken to avoid exposure. How the dose, route,
and duration of corticosteroid administration affect the risk of developing
a disseminated infection is not known. The contribution of the underlying
disease and/or prior corticosteroid treatment to the risk is also
not known. If exposed to chickenpox, prophylaxis with varicella zoster
immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis
with pooled intramuscular immunoglobulin (IG) may be indicated. (See
the respective package inserts for complete VZIG and IG prescribing
information.) If chickenpox develops, treatment with antiviral agents
may be considered. 4. Drug interaction with ritonavir. A
drug interaction study in healthy subjects has shown that ritonavir
(a highly potent cytochrome P450 3A4 inhibitor) can significantly
increase systemic fluticasone propionate exposure (AUC), resulting
in significantly reduced serum cortisol concentrations (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Drug
Interactions and PRECAUTIONS: Drug Interactions: Inhibitors of Cytochrome P450). During
postmarketing use, there have been reports of clinically significant
drug interactions in patients receiving fluticasone propionate and
ritonavir, resulting in systemic corticosteroid effects including
Cushing syndrome and adrenal suppression. Therefore, coadministration
of fluticasone propionate and ritonavir is not recommended unless
the potential benefit to the patient outweighs the risk of systemic
corticosteroid side effects. 5. FLOVENT HFA should not be used to treatacute
symptoms. FLOVENT HFA is not to be regarded as a bronchodilator
and is not indicated for rapid relief of bronchospasm.
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| dailymed-instance:indicatio... |
FLOVENT HFA Inhalation
Aerosol is indicated for the maintenance treatment of asthma as prophylactic
therapy in patients 4 years of age and older. It is also indicated
for patients requiring oral corticosteroid therapy for asthma. Many
of these patients may be able to reduce or eliminate their requirement
for oral corticosteroids over time. FLOVENT
HFA Inhalation Aerosol is NOT indicated for the relief of acute bronchospasm.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
FLOVENT-HFA
|